Herpes viruses are DNA viruses and among them are herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and various other human herpes viruses (HHV) such as HHV-6, HHV-7, and HHV-8. Herpes viruses are in general transmitted by person-to-person contact by infected body secretions. The infection by said viruses can cause various diseases in humans. The severity of infection depends on the virus type and can sometimes be relatively mild, but under certain circumstances can be fatal to the host.
For example, symptomatic HSV-1 infections are fairly benign in immunocompetent individuals as HSV-caused oropharyngeal sores tend to disappear spontaneously. Primary clinical manifestations of HSV-2 infection, which is mainly transmitted sexually, are anogenital lesions. Genital herpes affects one third of the world's population, and among people with human immunodeficiency virus (HIV) the incidence may be as high as 80 percent. HSV infections are particularly severe and even life-threatening to patients with acquired immune deficiency syndrome (AIDS). Only 20 percent of herpes seropositive persons have symptomatic infection. The rest of them are asymptomatic but nevertheless are able to shed the virus. In view of the high prevalence of genital herpes and its cofactor role in enhancing sex-borne HIV transmission the herpesviruses are of particular concern. Cytomegalovirus may cause eye infection which may result in blindness if left untreated. Varicella-zoster virus may cause dermatomal vesicular rash or shingles that can be quite painful. Other herpes viruses such HHV-8 were recently implicated to cause malignant diseases in humans such as lymphomas and Kaposi's sarcoma-tumors that are frequently found in persons infected with HIV. The presence of such tumors is comprised in the clinical definition of acquired immunodeficiency syndrome (AIDS)--a fatal clinical condition that is commonly associated with HIV infection.
Herpes virus infections are usually treated with nucleoside analogs such as acyclovir (ACV). Although ACV is relatively safe and non-toxic, its prophylactic use to suppress HSV shedding in the genital Although ACV is relatively safe and non-toxic, its prophylactic use to suppress HSV shedding in the genital tract would require repeated exposure to the drug and may thus favor the spread of drug-resistant strains. The need for alternative agents effective against ACV-resistant mutants and which can be used topically for prophylaxis of HSV is obvious. Ideally, one must identify an effective and safe compound that could afford barrier protection against herpesviruses in general and against HSV in particular.
It would also be preferable if such an agent were also useful against common microbial sexually transmitted diseases (STDs) and played a contraceptive role as well. As ACV is not suitable for these purposes alternative, multifunctional agents are needed. Nonoxynol-9 (N9), the most common spermicidal ingredient in topical vaginal formulations, initially appeared to fulfill this requirement. However, several lines of evidence exist indicating that N9 is less effective and more toxic than assumed originally.
Linear gramicidin or gramicidin D is an antibiotic first discovered in 1939 by Rene Dubos and has broad spectrum activity against gram-positive bacteria, fungi, and protozoa. Commercial gramicidin D preparation consists of a mixture of three pairs of gramicidins A, B, and C, making up approximately 80%, 6%, and 14% respectively. Each pair consists of 2 subspecies, one with valine in position one, comprising 80-95% of the component, and the other with isoleucine. Gramicidin does not irritate mucous membranes, is poorly absorbed through the skin, and it is still used today as one of the active ingredients in ophthalmic antimicrobial solutions, e.g., Neosporin. Gramicidin belongs to the porin type of antibiotics and acts by forming cation channels across the cell membrane which results in potassium efflux. Gramicidin has been used for over fifty years mainly as a broad spectrum topical antimicrobial, antifungal, and antiprotozoan agent. Cyclic or gramicidin S is used in the former Soviet Union (FSU) as an active ingredient of a spermicidal vaginal contraceptive and as antimicrobial agent. Gramicidin S is unrelated to gramicidin D as these two antiobiotics have different chemical structure and mode of action. Gramicidin S is a detergent and acts by lysing cell membranes in a manner similar to N9 detergent. The term "gramicidin" as used herein relates to the linear form of gramicidin. Gramicidin has been recently identified by this inventor as a potent anti-HIV agent as described in the U.S. Pat. No. 5,552,382 relating to the method of prevention of HIV infection. Gramicidin at 10 ng/ml concentration was active not only against lab strains of HIV but also against clinical isolates. However, the use of gramicidin against herpes viruses was not obvious as HIV and herpes viruses are not related genetically and replicate by completely different mechanisms. Thus, while the utility of gramicidin as an anti-HIV agent was known in the prior art, the utility of gramicidin as an anti-herpes agent was totally unpredictable.